Crohn's disease (CD) and ulcerative colitis (UC) are common manifestations of inflammatory bowel disease (IBD). These two debilitating disorders afflict approximately 1.4 million Americans and over 4 million people worldwide. Previous work from our lab has identified a novel sub-group of cellular proteins from the NLR family of pattern recognition receptors that function to negatively regulate inflammation and tumor development during IBD. We have previously shown that the NLR NLRP12 is a potent modulator of experimental colitis and inflammation driven tumorigenesis in pre-clinical mouse models. During IBD, NLRP12 modulates gastrointestinal inflammation through the attenuation of either canonical or non-canoincal NF-?B signaling. While the role of the canonical NF-?B signaling pathway during IBD is well established, the contribution of the non-canonical NF-?B cascade is relatively uncharacterized. Our previous findings indicate that a pair of chemokines associated with non-canonical NF-?B signaling is significantly up-regulated in the absence of NLRP12 and associated with increased IBD pathobiology in mice. These same chemokines are also dysregulated in human IBD patients. For example, our preliminary data revealed that the NLRP12 regulated chemokine CXCL13 is up-regulated 42- and 23-fold in CD and UC patients that are unresponsive to infliximab, respectively. Together, these data illustrate the importance of NLRP12 and non-canonical NF-?B signaling during IBD; however, the underlying mechanism/s is still unresolved. One hypothesis suggests that NLRP12 attenuates canonical NF-?B signaling during IBD; whereas, a second hypothesis that is supported by our preliminary data, indicates that NLRP12 inhibits the non-canoncial NF-?B signaling cascade. The apparent discrepancies in the hypothesized mechanisms can be reconciled by considering that the canonical NF-?B pathway can be significantly influenced by noncanoncial NF-?B signaling. Likewise, it is possible that these pathways are differentially modulated through cell type and/or temporal specific mechanisms that can significantly impact IBD pathogenesis. Here, I propose an extension to research project (K01-DK092355) to better evaluate these two prevailing hypotheses. The overall goal of this proposal is to generate a panel of mice that are deficient in canonical and non-canonical NF-?B signaling following cell specific Cre-recombinase disruption to better characterize the mechanism associated with NLRP12 modulation of IBD. NLRs with negative regulatory functions, such as NLRP12, and non-canonical NF-?B signaling during IBD represent areas that are currently understudied and not well defined. The mouse lines and data generated by the proposed studies will serve as preliminary data for a future R01 submission. The evaluation of these unique pathways in the context of IBD represent a novel direction that will contribute to future discoveries associated with immune system homeostasis in the gut and lead to new therapeutic strategies targeting these diseases.